Objective To elucidate the molecular mechanisms of the antibopolar action of lithium in the primate brain. ABSTRACT:The phosphoinositide signalling system is a widespread mechanism for transducing signals from neuro-transmitters, hormones, and growth factors to intracellular processes. We have made three discoveries related to phosphoinositide signalling with the antimanic-depression drug, lithium (1) In higher animal species (guinea pig, rabbit, rhesus monkey) and in human neuroblastoma cells, lithium increases acetylcholine-stimulated second messenger Ins(1,4,5)P3. (2) In the absence of added agonist, lithium raises extracellular glutamate in cerebrocortical slices, which, via activation of the NMDA receptor, raises Ins(1,4,5)P3. (3) Lithum appears to stimulate glutamate release in vivo in the frontal cortex of the rhesus monkey. Keywords lithium, glutamate, phosphoinositide signalling, NMDA receptor